MAPK15-ULK1 signaling regulates mitophagy of airway epithelial cell in chronic obstructive pulmonary disease

Airway epithelial mitochondrial oxidative stress and damage is an important pathology in chronic obstructive pulmonary disease (COPD). Mitophagy involves MAPK15-ULK1 signaling, the role of which is unknown in COPD. This study investigated MAPK15-ULK1 signaling in airway epithelial cells of COPD patients and its activation by cigarette smoke extract (CSE) in isolated human airway epithelial cells. Significant increased phosphorylation of MAPK15 and ULK1 (Ser555) was detected in the airway epithelium of COPD patients. This pathology was maintained in isolated primary COPD-epithelial cells. Compared to control cells, the protein expression of Beclin1 and the ratio of LC3II to LC3I were both significantly increased in COPD-epithelial cells. In human airway epithelial cells, CSE significantly increased the phosphorylation of MAPK15, ULK1 (Ser555), the expression of Beclin1, and the LC3II/LC3I ratio in a concentration- and time-dependent manner. Transfection with MAPK15 siRNA significantly inhibited the CSE-induced ULK1 (Ser555) phosphorylation in airway epithelial cells. Silencing of MAPK15 or ULK1 significantly reduced CSE-induced mitophagy and mitochondrial oxidative stress, thereby improving cell viability. In summary, cigarette smoke activated MAPK15-ULK1 signaling, thereby promoting mitophagy and mitochondrial oxidative stress in airway epithelial cells. This signaling pathway is activated in COPD-epithelial cells and therefore might present a novel therapeutic target for COPD